Calcium plays an indispensable role in cell permeability, the formation of bones and teeth, blood coagulation, transmission of nerve impulse, and normal muscle contraction. The concentration of calcium ions in the blood is, along with calcitriol and calcitonin, regulated mainly by parathyroid hormone (PTH). Extracellular calcium levels are directly affected by PTH through calcium uptake in kidney tubule cells and calcium transport to or from bone. Although calcium intake and excretion may vary, PTH serves through feedback mechanism to maintain a steady concentration of calcium in cells and surrounding fluids. When serum calcium lowers, the parathyroid glands secrete PTH, affecting the release of stored calcium. When serum calcium increases, stored calcium release is retarded through lowered secretions of PTH.
Osteoporosis is the most common form of metabolic bone disease and may be considered the symptomatic, fracture stage of bone loss (osteopenia). Although osteoporosis may occur secondary to a number of underlying diseases, 90% of all cases appear to be idiopathic. Postmenopausal women are particularly at risk for idiopathic osteoporosis (postmenopausal or Type I osteoporosis). Another high risk group for idiopathic osteoporosis is the elderly of either sex (senile or Type II osteoporosis). Osteoporosis has also been related to corticosteroid use, immobilization or extended bed rest, alcoholism, diabetes, gonadotoxic chemotherapy, hyperprolactinemia, anorexia nervosa, primary and secondary amenorrhea, and oophorectomy.
The complete or whole form of human PTH, (hPTH), is a unique 84 amino acid peptide (SEQ ID NO: 1), as is shown in FIG. 1. Researchers have found that this peptide has an anabolic effect on bone that involves a domain for protein kinase C activation (amino acid residues 28 to 34) as well as a domain for adenylate cyclase activation (amino acid residues 1 to 7). However, various catabolic forms of clipped or fragmented PTH peptides also are found in circulation, most likely formed by intraglandular or peripheral metabolism. For example, hPTH can be cleaved between amino acids 34 and 35 to produce a (1-34) PTH N-terminal fragment and a (35-84) PTH C-terminal fragment. Likewise, clipping can occur between either amino acids 36 and 37 or 37 and 38. Recently, a large PTH fragment referred to as “non-(1-84) PTH” has been disclosed which is clipped closer to the N-terminal end of PTH. (See LePage, R., et al., Clin. Chem. (1998); 44: 805-810.)
The present invention is based, in part, on the premise that there are two types of hormones (both secreted by the parathyroid gland) that are antagonists which exert control over the rate of bone turnover. CAP (cyclase activating PTH or PTH agonist), e.g., PTH1-84, operating through the PTH/PTHrp receptor accelerates bone turnover, and CIP (cyclase inactive PTH or PTH antagonist), frequently comprised of PTH7-84, operates through a C terminal PTH receptor and decelerates bone turnover.
A variety of therapeutic agents are available for the treatment of osteoporosis, and some agents are more appropriate for some subjects than others. As further described herein, treatment with one agent versus another may have detrimental health related implications. Thus, treatment options for osteoporosis patients should be individualized to maximize therapeutic potential and to minimize detrimental health related implications resulting from poor therapeutic agent choices. The present invention addresses this and other related needs in the art.
The present description further contemplates kits in accordance with the methods provided herein. Such kits comprise materials and instructions suitable for performing the present methods and the like.